Traumatic spinal cord injury (SCI) is a devastating condition for which there is no cure. Currently, there is no standard of care for traumatic brain injury or stroke. There is also no cure for stroke, and the only FDA approved treatment is tissue plasminogen activator (tPA), a thrombolytic agent with limited therapeutic benefit [Stroke and cerebrovascular accidents. World Health Organization, Circulation, 2009]. There is a need generally to provide therapies for all traumatic injuries to the central nervous system. The initial mechanical trauma, termed the primary injury, causes damage to blood vessels and localized cell death [C. H. Tator, Strategies for recovery and regeneration after brain and spinal cord injury. Injury Prevention 8 (2002) Iv33-Iv36.]. These in turn lead to excitotoxicity, inflammation, hemorrhage, vasospasm, and edema, which result in functional deficits in the patient [J. Krieglstein, Excitotoxicity and neuroprotection. Eur J Pharm Sci 5(4) (1997) 181-187; A. Scriabine, T. Schuurman, J. Traber, Pharmacological Basis for the Use of Nimodipine in Central Nervous- System Disorders. Faseb J 3(7) (1989) 1799-1806]. These pathological events can occur from days to months after injury and are known as the secondary injury [A. Arun, B. S. R. Reddy, In vitro drug release studies from the polymeric hydrogels based on HEA and HPMA using 4-{(E)-[(3Z)-3-(4-(acryloyloxy)benzylidene)-2-hexylidene]methyl}lphenyl acrylate as a crosslinker. Biomaterials 26(10) (2005) 1185-1193; M. D. Norenberg, J. Smith, A. Marcillo, The pathology of human spinal cord injury: Defining the problems. J Neurotraum 21(4) (2004) 429-440]. Both neuroregenerative and neuroprotective therapeutics are being pursued to limit the devastation that occurs after injury, yet their delivery remains challenging.
There are three common delivery strategies—systemic, pump/catheter, and bolus—yet each has its drawbacks. Systemic delivery is limited because most molecules cannot cross the blood-spinal cord barrier and those that do may have profound systemic side effects [C. H. Tator, Strategies for recovery and regeneration after brain and spinal cord injury. Injury Prevention 8 (2002) Iv33-Iv36]. The external pump/catheter system pumps drugs from a reservoir into the intrathecal space through a catheter. While a constant dose can be administered, this method is open to infection and has not been approved for long-term delivery in SCI patients in the USA. Bolus injection into the intrathecal space is compromised by cerebral spinal fluid (CSF) flow, which disperses the drug, thereby requiring repeated administration.
Much research effort has been devoted to improving the therapeutic efficacy and delivery of hydrophobic drugs which is often limited by low solubility [L. Zema, A. Maronii, A. Foppoli, L. Palugan, M. E. Sangalli, A. Gazzaniga, Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: An investigation into the mechanisms governing drug release. J Pharm Sci 96(6) (2007) 1527-1536; Z. G. He, D. F. Zhong, X. Y. Chen, X. H. Liu, X. Tang, L. M. Zhao, Development of a dissolution medium for nimodipine tablets based on bioavailability evaluation. Eur J Pharm Sci 21(4) (2004) 487-491; E. Lu, Z. Q. Jiang, Q. Z. Zhang, X. G. Jiang, A water -insoluble drug monolithic osmotic tablet system utilizing gum arabic as an osmotic, suspending and expanding agent. J Control Release 92(3)(2003) 375-382]. In solid pharmaceutical formulations, polymeric excipients similar to MC, such as hydroxypropyl methylcellulose or poly(vinylpyrrolidone), are incorporated into the drug particles to increase the solubility of sparingly soluble drugs [Z. G. He, D. F. Zhong, X. Y. Chen, X. H. Liu, X. Tang, L. M. Zhao, Development of a dissolution medium for nimodipine tablets based on bioavailability evaluation. Eur J Pharm Sci 21(4) (2004) 487-491; H. Wen, K. R. Morris, K. Park, Synergic effects of polymeric additives on dissolution and crystallization of acetaminophen. Pharmaceut Res 25(2) (2008) 349-358; B. C. Hancock, M. Parks, What is the true solubility advantage for amorphous pharmaceuticals? Pharmaceut Res 17(4) (2000) 397-404; M. E. Matteucci, B. K. Brettmann, T. L. Rogers, E. J. Elder, R. O. Williams, K. P. Johnston, Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Molecular Pharmaceutics 4(5) (2007) 782-793; S. L. Raghavan, A. Trividic, A. F. Davis, J. Hadgraft, Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm 212(2) (2001) 213-221]. This is typically achieved by disrupting the crystalline drug particle structure [B. C. Hancock, M. Parks, What is the true solubility advantage for amorphous pharmaceuticals? Pharmaceut Res 17(4) (2000) 397-404; M. E. Matteucci, B. K. Brettmann, T. L. Rogers, E. J. Elder, R. O. Williams, K. P. Johnston, Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Molecular Pharmaceutics 4(5) (2007) 782-793], thereby producing a less-stable amorphous drug particle that can be up to orders of magnitude more soluble than the crystalline drug [B. C. Hancock, M. Parks, What is the true solubility advantage for amorphous pharmaceuticals? Pharmaceut Res 17(4) (2000) 397-404; M. E. Matteucci, B. K. Brettmann, T. L. Rogers, E. J. Elder, R. O. Williams, K. P. Johnston, Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Molecular Pharmaceutics 4(5) (2007) 782-793; V. M. Rao, J. L. Haslam, V. J. Stella,Controlled and complete release of a model poorly water-soluble drug, prednisolone, from hydroxypropyl methylcellulose matrix tablets using (SBE)(7M )-beta-cyclodextrin as a solubilizing agent. J Pharm Sci 90(7) (2001) 807-816]. These polymeric excipients are also used as stabilizing additives in supersaturated solutions [M. E. Matteucci, B. K. Brettmann, T. L. Rogers, E. J. Elder, R. O. Williams, K. P. Johnston, Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Molecular Pharmaceutics 4(5) (2007) 782-793; S. L. Raghavan, A. Trividic, A. F. Davis, J. Hadgraft,Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm 212(2) (2001) 213-221; S. L. Raghavan, A. Trividic, A. F. Davis, J. Hadgraft, Effect of cellulose polymers on supersaturation and in vitro membrane transport of hydrocortisone acetate. Int J Pharm 193(2) (2000) 231-237; K. Yamashita, T. Nakate, K. Okimoto, A. Ohike, Y. Tokunaga, R. Ibuki, K. Higaki, T. Kimura, Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int J Pharm 267(1-2) (2003) 79-91; S. L. Raghavan, K. Schuessel, A. Davis, J. Hadgraft, Formation and stabilisation of triclosan colloidal suspensions using supersaturated systems. Int J Pharm 261(1-2) (2003) /153-158; U. Kumprakob, J. Kawakami, I. Adachi, Permeation enhancement of ketoprofen using a supersaturated system with antinucleant polymers. Biological & Pharmaceutical Bulletin 28(9) (2005) 1684-1688] and gels [S. L. Raghavan, A. Trividic, A. F. Davis, J. Hadgraft, Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm 212(2) (2001) 213-221; S. L. Raghavan, A. Trividic, A. F. Davis, J. Hadgraft, Effect of cellulose polymers on supersaturation and in vitro membrane transport of hydrocortisone acetate. Int J Pharm 193(2) (2000) 231-237] for oral and transdermal drug delivery, where a layer of adsorbed, “antinucleating” polymer on the surface of the nascent crystal is believed to inhibit further crystallization of the drug [X. G. Ma, J. Taw, C. M. Chiang, Control of drug crystallization in transdermal matrix system. Int J Pharm 142(1) (1996) 115-119; P. N. Kotiyan, P. R. Vavia, Eudragits: Role as crystallization inhibitors in drug -in-adhesive transdermal systems of estradiol. Eur J Pharm Biopharm 52(2) (2001) 173-180].
Given the limitations associated with current delivery strategies as described previously, a minimally-invasive injectable, thermally-responsive hydrogel comprised of hyaluronan (HA) and methylcellulose (MC) was designed for sustained and localized release. [D. Gupta, C. H. Tator, M. S. Shoichet, Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord. Biomaterials 27(11) (2006) 2370-2379]. This physical blend has been shown to be safe and provide greater neuroprotection when used to deliver erythropoietin to the intrathecal space than traditional delivery strategies such as intraperitoneal and intrathecal bolus [Kang C E, Poon P C, Tator C H, Shoichet M S, A New Paradigm for Local and Sustained Release of Therapeutic Molecules to the Injured Spinal Cord for Neuroprotection and Tissue Repair. Tissue Engineering Part A 15(3) (2009) 595-604].
U.S. parent patent application Ser. No. 11/410,831 describes a polymer blend comprising an inverse thermal gelling polymer and an anionic polymer, for example HAMC that exists as a gel. This polymer mixture has a shorter time to gelation than the inverse gelling polymer alone, and may be used alone or as a drug delivery vehicle for many applications. In particular, the polymer mixture can be used for localized, targeted delivery of pharmaceutical agents upon injection providing sustained release. A particular use of this polymer mixture is in delivery of a therapeutic agent in a highly localized, targeted manner, wherein the polymer matrix-contained therapeutic agent is able to circumvent the blood-spinal cord barrier or blood-brain barrier and enter the target tissue directly. This can be achieved, for example, by injection of the matrix (or mixture) into the intrathecal space, a fluid-filled space wherein cerebral spinal fluid flows. U.S. Pat. No. 6,335,035 ('035) to Drizen, et al. is a divisional of U.S. Pat. No. 6,063,405 to Drizen et al. which teaches sustained release compositions comprising a drug dispersed within a polymer matrix, methods of producing the same and treatments with the complex. The '035 patent discloses a sustained drug delivery system, which comprises a drug dispersed within a polymer matrix solubilized or suspended in a polymer matrix. The polymer matrix is composed of a highly negatively charged polymer material selected from the group consisting of polysulfated glucosoglycans, glycoaminoglycans, mucopolysaccharides and mixtures thereof, and a nonionic polymer selected from the group consisting of carboxymethylcellulose sodium, hydroxypropylcellulose and mixtures thereof. Nonionic polymers are generally used in amounts of 0.1% to 1.0% and preferably from 0.5% to 1.0%. Nonionic polymers in amounts above 1.0% are not used as they result in the formation of a solid gel product when employed in combination with an anionic polymer.
U.S. Pat. No. 6,692,766 to Rubinstein et al. concerns a controlled release drug delivery system comprising a drug which is susceptible to enzymatic degradation by enzymes present in the intestinal tract; and a polymeric matrix which undergoes erosion in the gastrointestinal tract comprising a hydrogel-forming polymer selected from the group consisting of (a) polymers which are themselves capable of enhancing absorption of said drug across the intestinal mucosal tissues and of inhibiting degradation of said drug by intestinal enzymes; and (b) polymers which are not themselves capable of enhancing absorption of said drug across the intestinal mucosal tissues and of inhibiting degradation of said drug by intestinal enzymes.
U.S. Pat. No. 6,716,251 to Asius et al. discloses an injectable implant for filling up wrinkles, thin lines, skin cracks and scars for reparative or plastic surgery, aesthetic dermatology and for filling up gums in dental treatment. The invention concerns the use of biologically absorbable polymer microspheres or micro particles suspended in a gel.
U.S. Pat. No. 6,586,493 to Massia et al. discloses hyaluronate-containing hydrogels having angiogenic and vascularizing activity and pre-gel blends for preparing the hydrogels. The hydrogels contain a cross-linked matrix of a non-angiogenic hyaluronate and a derivatized polysaccharide material, in which cross-linking is effected by free-radical polymerization. JP2003-342197 discloses a heat gelling pharmaceutical preparation containing methylcellulose and hyaluronic acid that is liquid at room temperature and gels upon administration to the eye. The literature also teaches the properties of gel-forming polymer mixtures and their use as drug delivery vehicles (Xu et al. Langmuir, (2004) 20(3): 646-652, Liang et al. Biomacromolecules, 2004. 5(5):1917-25, Ohya et al. Biomacromolecules (2001) 2:856-863, Cho et al. International Journal of Pharmaceutics (2003) 260:83-91, Kim et al. Journal of Controlled Release (2002) 80:69-77, Tate et al. Biomaterials (2001) 22:1113-1123, and Silver et al., Journal of Applied Biomaterials (1994) 5:89-98).